Method for bowel preparation

ABSTRACT

The present invention provides methods for facilitating cleansing of the gastrointestinal tract of a patient prior to a diagnostic, surgical or therapeutic procedure. The methods can improve patient compliance, and thus, efficacy of the preparation. Specifically, the present methods make the gastrointestinal tract preparation composition palatable for the patient to consume. For example, for a patient preparing to undergo colonoscopy, the present methods make the bowel preparation solution taste significantly less salty.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/394,877 filed Apr. 25, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/793,257 filed Oct. 25, 2017, which is acontinuation of U.S. patent application Ser. No. 15/456,028 filed onMar. 10, 2017, which is a continuation of U.S. patent application Ser.No. 15/165,948 filed on May 26, 2016, now U.S. Pat. No. 9,629,917, whichis a continuation of U.S. patent application Ser. No. 14/963,616 filedon Dec. 9, 2015, now U.S. Pat. No. 9,352,044, which is a continuation ofU.S. patent application Ser. No. 13/708,430 filed on Dec. 7, 2012, nowU.S. Pat. No. 9,238,075, which claims the benefit of U.S. ProvisionalApplication No. 61/568,131 filed on Dec. 7, 2011. The entire contents ofall of these applications are incorporated by reference in theirentirety.

The present invention relates to methods for cleansing thegastrointestinal tract of a patient prior to a diagnostic, surgical ortherapeutic procedure. In particular, this invention makes thegastrointestinal tract preparation composition palatable.

BACKGROUND OF THE INVENTION

Colorectal cancer is the third most common cancer amount both men andwomen in the world. Early detection of colorectal cancer great improvesthe chances of a cure. Colonoscopies are widely recognized as the goldstandard for colorectal cancer screening. Rex et al., Colorectal cancerprevention 2000: Screening recommendations of the American College ofGastroenterology. Am J. Gastroenterol. 2000; 95: 868-877. Colonoscopiesare also frequently used to diagnose many other gastrointestinalpathologies.

Despite the effectiveness of colonoscopies, compliance is often an issueamong patients, mainly due to the bowel preparation procedure where thepatient is required to drink large volumes of a foul-tasting solution.For the colonoscopy test to be performed properly, the colon must befree of solid matter. Thus, prior to undergoing a colonoscopy, thepatient needs to ingest bowel preparation solutions to empty the bowel.The preparations typically contain large amounts of polyethylene glycoland electrolytes (e.g., sodium chloride, sodium bicarbonate, and/orpotassium chloride). A large amount (e.g., 4 liters) of this salty andfoul-tasting solutions must be taken orally to cleanse the bowel. Thebowel preparation procedure is often described as very unpleasant bycolonoscopy recipients. U.S. Patent Publication No. 20090053304.

Inadequate preparations are responsible for up to ⅓ of all incompleteprocedures, preclude up to 10% of examinations, and negatively impactthe rate of polyp and adenoma detection. Technology Status EvaluationReport: Colonoscopy Preparation, Gastrointestinal Endoscopy, 2009,69(7): 1201-1209. Because of the importance of proper cleansing of thecolon, there has been an increased focus on the palatability of thesolution as a factor of patient compliance. The Prep Is Worse Than TheProcedure, Harvard Health Newsletters, Jan. 1, 2010.

The ideal bowel preparation is safe, effective and acceptable topatients with negligible discomfort. Because it is safer and moreeffective than other prep solutions, polyethylene glycol (PEG) solutionhas been used as the so-called “gold standard” for colonoscopy. However,despite the fact that PEG solutions are well tolerated by patients,5%-15% of patients do not complete the preparation because of poorpalatability and/or large volume. R H Hawes et al., Consensus Documenton Bowel Preparation before Colonoscopy, Gastrointestinal Endoscopy2006, 63(7): 894-909. Efforts have been made to make bowel preparationsolutions more palatable with the addition of flavorings. For example,PEG solutions are available in multiple flavors, such as cherry,citrus-berry, lemon-lime, orange and pineapple. Sulfate salts have beenremoved from gastrointestinal tract preparation solutions such asHalfLytely® and NuLYTELY® resulting in a less salty taste and a lesspungent “rotten egg” smell”. Water, ginger ale, Gatorade, CrystalLite,and carbohydrate-electrolyte solutions have also been used to improvethe taste of these solutions. However, flavoring packages do notsignificantly change palatability in terms of the saltiness and overalltaste. Furthermore, improved flavor does not necessarily equate toimproved tolerance. In fact, when flavoring additions is added, specialcare must be taken to avoid altering the osmolarity of the preparationor adding substrates to the preparation which can metabolize intoexplosive gases or alter the amount of water and salts absorbed. R HHawes et al., Consensus Document on Bowel Preparation beforeColonoscopy, Gastrointestinal Endoscopy, 2006, 63(7):894-909.

Therefore, there is still a need for development of palatable bowelpreparation compositions that would achieve effective cleansing withimproved tolerability and reduced adverse effects.

Miraculin is a glycoprotein derived from the miracle fruit plant(Richadella dulcifica or Synepalum dulcificum) native to Ghana, WestAfrica. Although not sweet itself, miraculin has an effect of modifyingthe sourness of a food to taste sweet without the addition of sugar orartificial sweeteners. Sour substances such as lemons and limes tastesweet after a person eats the flesh of the berry or after freeze-driedextracts of miraculin are dissolved on the person's tongue. This sweeteffect can last up to one to two hours or longer.

Miraculin modifies the perception of taste by making the sweet receptorsmore responsive to acids instead of only to sugars and other sweetsubstances. R H Cagan, Chemostimulatory Protein: A New Type of TasteStimulus, Science 181(94):32-5 (Jul. 6, 1973); Ravi Kant, SweetProteins-Potential Replacement for Artificial Low Calorie Sweeteners,Nutrition Journal, 2005, 4:5. Miraculin is also effective in inducing ataste of sweetness in mixtures that includes a salty tastant. Capitanioet al., Mixing Taste Illusions: The Effects of Miraculin on Binary andTrinary Mixtures, Journal of Sensory Studies, 26 (2011) 54-61. However,it was also reported that, although the miracle fruit made sour foodstaste sweet, it slightly enhanced other flavors, such as the degree ofsaltiness. See, Miracle Fruit Research at Dulci Berry Website, 2012.

The present invention provides methods to use, e.g., miraculin ormiracle berry, to make the gastrointestinal tract preparationcomposition palatable. The use of the present invention is expected tohave better patient compliance resulting in the ingestion of thecomplete bowel preparation and cleaner colonic mucosa.

SUMMARY

The present invention provides for a method for cleansing thegastrointestinal tract of a patient comprising the steps of: (a)determining the pH of a gastrointestinal tract preparation compositionwhich has a salty taste, and adjusting the pH to range from about 3 toabout 6.4 if necessary; (b) providing a taste-modifying substance to thepatient; and (c) administering orally the gastrointestinal tractpreparation composition to the patient, wherein the salty taste of thegastrointestinal tract preparation composition is reduced by at leastabout 20%, at least about 30%, at least about 50%, or at least about 70%compared to the salty taste of the gastrointestinal tract preparationcomposition had the taste-modifying substance not been provided. Thestep to determine the pH of the gastrointestinal tract preparationcomposition may be carried out prior to or after the step of providing ataste-modifying substance to the patient. The desired pH may range fromabout 4 to about 6.4. The desired pH may range from about 4.5 to about5. In a specific embodiment, the desired pH is about 4.8.

For example, the present invention provides methods for cleaning theintestine (e.g., the colon). The present gastrointestinal tractpreparation composition may be a bowel preparation solution.

The gastrointestinal tract may be cleansed prior to carrying out adiagnostic, therapeutic and/or surgical procedure on the patient. Forexample, the gastrointestinal tract is cleansed prior to an endoscopy,such as a colonoscopy or sigmoidoscopy. The gastrointestinal tract maybe cleansed prior to a barium enema examination, capsule endoscopy,colon surgery or gastrointestinal tract surgery.

Non-limiting examples of the taste-modifying substance includethaumatin, monellin, mabinlin, brazzein, pentadin, curculin, neuculin,miraculin and mixtures thereof. The taste-modifying substance can beprovided in the form of a capsule, a tablet, a pill, granules, powders,a pellet, a solids mixture, a solution, a dispersion, an emulsion, apaste, an extract, or an isolate from a natural source.

The taste-modifying substance may be a sour taste-modifying agent, suchas miraculin. Miraculin can be given in any suitable form, such asmiracle fruit, flesh of miracle fruit, miracle fruit granules, miracleberry, miracle berry extracts, miracle berry tablets, miracle fruittablets, or miraculin produced by a genetically modified organism.

The taste-modifying substance may be provided to the patient from about1 minute to about 2 hours, from 5 minutes to about 1 hour, from about 5minutes to about 30 minutes, from about 1 minute to about 5 minutes orfrom about 10 minutes to about 15 minutes before the gastrointestinaltract preparation composition is administered.

The pH of the gastrointestinal tract preparation composition may beadjusted by at least an inorganic acid or an organic acid. For example,the acids include, but are not limited to, citric acid, acetic acid,ascorbic acid, phosphoric acid, malic acid, succinic acid, formic acid,fumaric acid, maleic acid, or mixtures thereof. The pH of thegastrointestinal tract preparation composition may also be adjusted byammonium hydroxide, sodium carbonate, potassium carbonate, sodiumbicarbonate, carbon dioxide, or mixtures thereof.

The gastrointestinal tract preparation composition may contain apotassium salt, a sodium salt, a calcium salt, an ammonium salt ormixtures thereof. For example, the gastrointestinal tract preparationcomposition comprises sodium chloride, potassium chloride, and sodiumbicarbonate (sodium hydrogen carbonate), sodium sulfate or mixturesthereof. The gastrointestinal tract preparation composition may includeat least one sodium phosphate. The gastrointestinal tract preparationcomposition may contain at least one alkali metal (e.g., sodium andpotassium) salt, and/or at least one alkaline earth metal (e.g.,magnesium or calcium) salt.

The gastrointestinal tract preparation composition may comprisepolyethylene glycol (PEG). The gastrointestinal tract preparationcomposition may be a solution. The volume of the gastrointestinal tractpreparation composition can range from about 0.1 liters to about 5liters or from about 1 liter to about 4 liters.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph demonstrating the average perception of saltiness ofthe bowel preparation solution for the subjects with and without miracleberry tablets.

FIG. 2 is a sample patient questionnaire after tasting the bowelpreparation solution prior to addition of a flavor pack and use ofmiracle fruit.

FIG. 3 is a sample patient questionnaire after tasting the bowelpreparation solution with use of miracle fruit and addition of a flavorpack to the bowel preparation solution.

FIG. 4 is a sample of post-preparation patient questionnaire (i.e., tobe completed after completion of the preparation).

FIG. 5 shows the average rating in each of the three categories(sweetness, saltiness and overall palatability) for each of the sixtasting samples after the four subjects tasted them without miracleberry tablets.

FIG. 6 shows the average rating in each of the three categories(sweetness, saltiness and overall palatability) for each of the sixtasting samples after the four subjects tasted them with miracle berrytablets.

FIG. 7 is a graph for Example 5 demonstrating the average perception ofsweetness and overall palatability for each of the 11 subjects with andwithout miracle berry tablets.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for cleansing thegastrointestinal tract of a patient prior to a diagnostic, surgical ortherapeutic procedure. The methods can improve patient compliance, andthus, efficacy of the preparation. Specifically, the present methodsmake the gastrointestinal tract preparation composition palatable forthe patient to consume. For example, for a patient preparing to undergocolonoscopy, the present methods make the bowel preparation solutiontaste significantly less salty.

The present invention provides a method for cleansing thegastrointestinal tract of a patient. The method has the following steps:(a) determining the pH of a gastrointestinal tract preparationcomposition, and adjusting the pH to range from about 3 to about 6.4 ifnecessary (i.e., the pH needs to be adjusted if the pH of thepreparation composition falls outside of the desired range, e.g., fromabout 3 to about 6.4, or other ranges as disclosed herein); (b)providing a taste-modifying substance to the patient; and (c)administering orally the gastrointestinal tract preparation compositionto the patient.

The present invention further provides a method for cleansing thegastrointestinal tract of a patient. The method has the following steps:(a) determining the pH of a gastrointestinal tract preparationcomposition which has a salty taste, and adjusting the pH to range fromabout 3 to about 6.4 if necessary (i.e., the pH needs to be adjusted ifthe pH of the preparation composition falls outside of the desiredrange, e.g., from about 3 to about 6.4, or other ranges as disclosedherein); (b) providing a taste-modifying substance to the patient; and(c) administering orally the gastrointestinal tract preparationcomposition to the patient, wherein the salty taste of thegastrointestinal tract preparation composition is reduced by at leastabout 20% compared to the salty taste of the gastrointestinal tractpreparation composition had the taste-modifying substance not beenprovided. The step to determine the pH of the gastrointestinal tractpreparation composition can be carried out prior to or after the step ofproviding a taste-modifying substance to the patient.

The taste-modifying substance is preferably miraculin.

The desired pH range may be from about 1 to about 6.9, from about 2 toabout 6.4, from about 2.5 to about 6.4, from about 3 to about 6.4, fromabout 4 to about 6.4, from about 5 to about 6.4, from about 3 to about6, from about 3 to about 5.5, or from about 3 to about 5. In a preferredembodiment, the desired pH ranges from about 4.5 to about 5. In anotherpreferred embodiment, the desired pH is about 4.8.

The gastrointestinal tract preparation composition of the presentinvention is administered orally, and may be used to prepare any part(s)of the gastrointestinal tract, including, but not limited to, theesophagus, stomach, intestine (or bowel) such as the small intestine andthe large intestine including cecum, colon and rectum. For example, thepresent methods may be used to empty the bowel.

The method of the present invention may be used to cleanse thegastrointestinal tract prior to a diagnostic, therapeutic and/orsurgical procedure. Non-limiting examples of the surgical proceduresinclude a colon surgery and a gastrointestinal tract surgery.Non-limiting examples of the diagnostic procedures include a bariumenema examination, a capsule endoscopy, an endoscopy such as acolonoscopy or sigmoidoscopy. Colonoscopy can be conventionalcolonoscopy or virtual colonoscopy. Heiken et al., Virtual colonoscopyfor colorectal cancer screening: current status, November 2005, CancerImagine (International Cancer Imaging Society), 5 (Spec No A):S133-S139. The method of the present invention may be used in thetreatment of acute gastrointestinal infections, for example bacterial orviral gastroenteritis. Colon cleansing is also useful for preventinginfection after surgery on the lower intestine.

The taste-modifying substance may be provided to the patient from about1 minute to about 3 hours, from about 1 minute to about 2 hours, fromabout 5 minutes to about 2 hours, from about 5 minutes to about 1.5hours, from about 5 minutes to about 1 hour, from about 5 minutes toabout 45 minutes, from about 5 minutes to about 30 minutes, from about 5minutes to about 15 minutes, or from about 10 minutes to about 15minutes before the gastrointestinal tract preparation composition isadministered.

The present invention also provides for a method for modifying the tasteof a liquid composition. The method has the following steps: (a)determining the pH of the liquid composition which has an undesirabletaste, and adjusting the pH to range from about 3 to about 6.4 ifnecessary (i.e., if the pH of the liquid composition falls outside ofthe range of from about 3 to about 6.4, or other desired pH ranges asdisclosed herein); (b) providing a taste-modifying substance to asubject; and (c) providing the liquid composition to the subject,wherein the undesirable taste of the liquid composition is reduced by atleast about 20% compared to the undesirable taste of the liquidcomposition had the taste-modifying substance not been provided. Thestep to determine the pH of the liquid composition can be carried outprior to or after the step of providing a taste-modifying substance tothe subject.

The liquid compositions include, but are not limited to,gastrointestinal tract preparation compositions, oral care compositionsand pharmaceutical compositions.

Perception of one or more tastes by a subject (such as a patient) may beassessed using suitable questionnaires or by personal interviews. Forexample, immediately after a subject consumes (or tastes) agastrointestinal tract preparation composition (or other liquidcompositions), he/she is asked to finish a questionnaire. In thequestionnaire, the subject is required to judge the perceived saltytaste (or other undesirable taste) intensity of the composition using,for example, a scale of 0 to 10 (or a scale of 0 to 100, a scale of 0 to5, a scale of 0 to 9, etc.). The subject will be instructed that “0”represents “no intensity” or “minimal intensity” (i.e., no or minimalsalty taste or other undesirable taste) whereas “10” (or “100” etc.)represents the “highest intensity” of the salty taste (or otherundesirable taste).

As taste is inherently subjective, the questionnaire or interviewdescribed above gives taste ratings that can be compared on the samepatient or subject. The reduction in the undesirable taste (e.g., thesalty taste) may be assessed by comparing the patient's (or subject's)taste rating when a taste-modifying substance was provided with the onewhen a taste-modifying substance was not provided. For example, if thetaste rating without a taste-modifying substance is T₁ and the tasterating with a taste-modifying substance is T₂, the percentage reductionin the undesirable taste may be calculated as follows:

(T ₁ −T ₂)/T ₁*100%

The undesirable taste of a liquid composition may be reduced by at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90%, compared to the undesirable taste of the liquid compositionhad the taste-modifying substance not been provided.

In some embodiments, the salty taste of the gastrointestinal tractpreparation composition may be reduced by at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70%, at least about 80%, at least about 90%, compared tothe salty taste of the gastrointestinal tract preparation compositionhad the taste-modifying substance not been provided.

One or more tastes can also be rated using the Thurstonian scale. AThurstonian model is a latent variable model for describing the mappingof some continuous scale onto discrete, possibly ordered categories ofresponse. In the model, each of these categories of response correspondsto a latent variable whose value is drawn from a normal distribution,independently of the other response variables and with constantvariance. Lawless et al., (1984), Direct and indirect scaling of sensorydifferences in simple taste and odor mixtures, J. Food Sci., 49, 44-51.Durlach, et al., (1969) Intensity Perception. I. Preliminary Theory ofIntensity Resolution, Journal of the Acoustical Society of America, 46(2): 372-383. Dessirier et al., 1998, Comparison of d′ values for the2-AFC (paired comparison) and 3-AFC discrimination methods: Thurstonianmodels, sequential sensitivity analysis and power, Food Quality andPreference, 10 (1): 51-58. Frijter, J. E. R., (1980) Three-stimulusprocedures in olfactory psychophysics: an experimental comparison ofThurstone-Ura and three-alternative forced choice models of signaldetection theory, Perception & Psychophysics, 28 (5): 390-7. Gridgement,N. T., (1970) A Reexamination of the Two-Stage Triangle Test for thePerception of Sensory Differences, Journal of Food Science, 35 (1).Frijters, J. E. R., (1979) The paradox of discriminatorynondiscriminators resolved, Chemical Senses & Flavor 4 (4): 355-8.Valentin et al., Taste-odour interactions in sweet taste perception, In:Spillane W J, editor, Optimising sweet taste in foods. Cambridge (UK):Woodhead Publishing; 2006: 66-84.

Other rating scales can also be used in the present invention,including, but not limited to, intensity scales, just-about-right (JAR)scales and hedonic scale. In intensity scales, intensity ratingquestions ask respondents to rate the strength of a sensory attribute,for example, its saltiness, on a scale from “low” to “high”. Injust-about-right scales, just-about-right questions ask respondents torate whether the level of a sensory attribute, for example, itssaltiness, is “too high”, “just right” or “too low”. Popper et al., Theeffect of attribute questions on overall liking ratings, Food Qualityand Preference, 15 (2004) 853-858. Peryam et al., Advanced taste-testmethod, Food Eng., 1952, 24:58-61. Lim et al., Derivation and Evaluationof a Labeled Hedonic Scale, Chem. Senses, 34: 739-751, 2009. Gregson, R.A. M., A Rating-Scale Method for Determining Absolute Taste Thresholds,Journal of Food Science, 1962, 27: 376-380.

An exemplary intensity scale and an exemplary five-point JAR scale areshown in Table 1.

TABLE 1 Intensity (nine-point) JAR (five-point) Extremely weak Much tooweak A little too weak Just about right A little too strong Much toostrong Extremely strong

The intensity of saltiness, sweetness, palatability or other tastes canbe rated on a line scale, e.g., an unstructured or structured linescale, or other suitable line scales. In one embodiment, the ratingscale is a 10-cm (or any other suitable length) visual analog scale withthe anchors being “none” and “extremely strong”. All ratings reported inthe visual analog scale are then converted to a 100-point scale bymeasuring the length of the segment marked by the test subject.Stevenson et al., Confusing tastes and smells: how odours can influencethe perception of sweet and sour taste? Chem. Senses, 1999, 24: 624-635.

As used herein, the term “taste” refers to any taste including the fivebasic tastes (i.e., sweet, sour, salty, bitter and umami) and othertastes such as tart, alkaline, astringent, tangy, dry, sharp, cool,warm, hot, burning, acidic, spicy, pungent, kokumi, savory, tinglingand/or metallic. Such taste shall include any and all taste(s) as wellas any and all aftertaste(s). The list above is not all inclusive as oneskilled in the art would recognize.

As used herein, the term “taste-modifying substance” or “taste-modifyingagent” refers to any substance that is able to modify the perception ofat least one taste during consumption of a gastrointestinal tractpreparation composition (or a liquid composition). They may act tomodify the perception of a taste or may affect the taste profile. Theterm “modify” means to change, alter, modulate, diminish, lessen,reduce, subdue, limit, intensify, supplement or potentiate. For example,a sour taste-modifying agent may modify the perception of a sour taste;a salty-modifying agent may modify the perception of a salty taste. Ataste-modifying substance may or may not possess a taste(s) of its own.

A taste-modifying substance may function by modulating the activity oftaste receptor cells and/or the taste signaling pathway in a mammal.Specifically, taste is perceived through sensory cells located in thetaste buds. Different signaling mechanisms sense the primary tastes ofsalty, sour, sweet, bitter and umami. Eventually a nerve impulse istriggered in the brain that is sensed as one of these primary tastes.For instance, in some cases, taste-modifying substances may bind totaste receptors, such as sweet taste receptors, which thereby modify theperception of the sweet taste. In other embodiments, taste-modifyingsubstances may block taste receptors, such as salty receptors, whichsuppress the perception of a salty taste.

In some embodiments, the blocking of an undesirable taste may allow anincreased sensation of another taste. For example, an increased sweetsensation that is perceived by the addition of a taste-modifyingsubstance may diminish a salty taste.

The effect of a taste-modifying substance to modify the perception of ataste may or may not depend on its concentration. A taste-modifyingsubstance may be used alone or in combination with other taste-modifyingsubstance(s). When two or more taste-modifying substances are used, theymay act additively or synergistically.

There may exist differences in taste perception between individuals. Forexample, there can be more than one perception of a single taste,whether such taste is a basic taste or another taste. For example, theremay be a number of different “salty” tastes that can be noted by someindividuals. U.S. Pat. No. 6,015,792.

The taste-modifying substance of the present invention may be a sweettaste-modifying agent, a sour taste-modifying agent, a saltytaste-modifying agent, a bitter taste-modifying agent, an umamitaste-modifying agent, etc.

Non-limiting examples of sweet taste-modifying agents include:

(a) protein: thaumatin, monellin, mabinlin, brazzein, pentadin,curculin, neuculin, miraculin and egg white lysozyme;

(b) water-soluble sweetening agents such as dihydrochalcones, stevia,steviosides, rebaudioside A, further steviol glycosides such asdulcoside and/or rubusoside, glycyrrhizin, dihydroflavenol; sugaralcohols (or polyols, such as sorbitol, mannitol, maltitol, xylitol,glycerol, erythritol, galactitol, hydrogenated isomaltulose, lactitol,hydrogenated starch hydrolysate, L-aminodicarboxylic acid aminoalkenoicacid ester amides, and mixtures thereof); monosaccharides, including butnot limited to, aldoses and ketoses beginning with trioses such asglucose, galactose, and fructose; compounds generically known as sugarsincluding, but not limited to, mono-, di- and oligosaccharides such assucrose, maltose, lactose, etc; carbohydrates and polysaccharidesincluding, but not limited to, polydextrose and maltodextrin;

(c) water-soluble artificial sweeteners such as soluble saccharin salts,i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium,ammonium or calcium salt of3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide, the potassiumsalt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide(Acesulfame-K), the free acid form of saccharin, 1,6-dichloro-1,6-dideoxy-beta-D-fructofuranosyl-4-chloro-4-deoxy-alpha-D-galactopyranoside(Sucralose), 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide(Acesulfame), cyclohexylsulfamic acid (Cyclamatee),N-(L-aspartyl)-N′(2,2,5,5,tetramethylcyclopentanoyl)1,1-diaminoethaneand its related compounds, guanidinium class sweeteners, dihydrochalconeclass sweeteners, stevioside, and their physiologically acceptablesalts, and mixtures thereof;

(d) dipeptide based sweeteners, such as L-aspartic acid derivedsweeteners, such as L-aspartyl-L-phenylalanine methyl ester (Aspartame),L-alphaaspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamidehydrate (Alitame), N—[N-(3,3-dimethylbutyl)-L-aspartyl]-L-phenylalanine1-methyl ester (Neotame), methyl esters of L-aspartyl-L-phenylglycerineand L-aspartyl-L-2,5-dihydrophenyl-glycine,L-aspartyl-2,5-dihydro-L-phenylalanine;L-aspartyl-L-(1-cyclohexen)-alanine, and mixtures thereof;

(e) water-soluble sweeteners derived from naturally occurringwater-soluble sweeteners, such as chlorinated derivatives of ordinarysugar (sucrose), e.g., chlorodeoxysugar derivatives such as derivativesof chlorodeoxysucrose or chlorodeoxygalactosucrose, known, for example,under the product designation of Sucralose; examples ofchlorodeoxysucrose and chlorodeoxygalactosucrose derivatives include butare not limited to: 1-chloro-1′-deoxysucrose;4-chloro-4-deoxy-alpha-D-galactopyranosyl-alpha-D-fructo furanoside, or4-chloro-4-deoxygalactosucrose;4-chloro-4-deoxy-alpha-D-galactopyranosyl-1-chloro-1-deoxy-beta-D-fructo-furanoside,or 4,1′-dichloro-4,1′-dideoxygalactosucrose; 1′,6′-dichloro1′,6′-dideoxysucrose;4-chloro-4-deoxy-alpha-D-galactopyranosyl-1,6-dichloro-1,6-dideoxy-beta-D-fructofuranoside,or 4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose;4,6-dichloro-4,6-dideoxy-alpha-D-galactopyranosyl-6-chloro-6-deoxy-beta-D-fructofuranoside,or 4,6,6′-trichloro-4,6,6′-trideoxygalactosucrose;6,1′,6′-trichloro-6,1′,6′-trideoxysucrose;4,6-dichloro-4,6-dideoxy-alpha-D-galacto-pyranosyl-1,6-dichloro-1,6-dideo-xy-beta-D-fructofuranoside,or 4,6,1′,6′-tetrachloro-4,6,1′,6′-tetradeoxygalacto-sucrose; and4,6,1′,6′-tetradeoxy-sucrose, and mixtures thereof.

Additional, non-limiting examples of the sweet taste-modifying substanceinclude oslandin, polypodoside A, strogin, selligueanin A,dihydroquercetin-3-acetate, perillartin, telosmoside A₁₅, periandrinI-V, pterocaryosides, cyclocaryosides, mukuroziosides, trans-anethol,trans-cinnamaldehyde, bryosides, bryonosides, bryonodulcosides,camosiflosides, scandenosides, gypenosides, trilobtain, phloridzin,dihydroflavanols, hematoxylin, cyanin, chlorogenic acid, albiziasaponin,telosmosides, gaudichaudioside, mogrosides, hernandulcin, glycyrrhetinicacid, monoammonium glycyrrhizinate, licorice glycyrrhizinates, citrusaurantium, alapyridaine, alapyridaine(N-(1-carboxyethyl)-6-(hydroxymethyl)pyridinium-3-ol) inner salt,gymnemic acid, cynarin, glupyridaine, pyridinium-betain compounds,neohesperidin dihydrochalcone, trehalose, vanilla oleoresin, vanillin,monatin (2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid) and itsderivatives; Lo han guo (also referred to as “Lo han kuo”); Furaneol(2,5-dimethyl-4-hydroxy-3(2H)-furanone) and derivatives (e.g.homofuraneol, 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone), homofuronol(2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and derivatives (e.g.ethylmaltol), coumarin and derivatives, gamma-lactones (e.g.gamma-undecalactone, gamma-nonalactone), delta-lactones (e.g.4-methyldeltalactone, massoilactone, deltadecalactone, tuberolactone),methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or2)-methyl-3(2H)furanone 2-hydroxy-3-methyl-2-cyclopentenones,3-hydroxy-4,5-dimethyl-2(5H)-furanone, fruit esters and fruit lactones(e.g. acetic acid-n-butyl ester, acetic acid isoamyl ester, propionicacid ethyl ester, butyric acid ethyl ester, butyric acid-n-butyl ester,butyric acid isoamyl ester, 3-methyl-butyric acid ethyl ester,n-hexanoic acid ethyl ester, n-hexanoic acid allyl ester, n-hexanoicacid-n-butyl ester, n-octanoic acid ethyl ester,ethyl-3-methyl-3-phenylglycidate, ethyl-2-trans-4-cis-decadienoate),4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4-hexane,2,6-dimethyl-5-hepten-1-al, 4-hydroxycinnamic acid,4-methoxy-3-hydroxycinnamic acid, 3-methoxy-4-hydroxycinnamic acid,2-hydroxycinnamic acid, vanillic acid, homovanillic acid,vanillomandelic acid and phenylacetaldehyde; monoammoniumglycyrrhizinate, licorice glycyrrhizinates, citrus aurantium,alapyridaine, alapyridaine(N-(1-carboxyethyl)-6-(hydroxymethyl)pyridinium-3-ol) inner salt,gymnemic acid, glupyridaine, pyridinium-betain compounds, neotame,neohesperidin dihydrochalcone, tagatose, trehalose, compounds thatrespond to G-protein coupled receptors (T2Rs and T1Rs), 2-hydroxybenzoicacid (2-HB), 3-hydroxybenzoic acid (3-HB), 4-hydroxybenzoic acid (4-HB),2,3-dihydroxybenzoic acid (2,3-DHB), 2,4-dihydroxybenzoic acid(2,4-DHB), 2,5-dihydroxybenzoic acid (2,5-DHB), 2,6-dihydroxybenzoicacid (2,6-DHB), 3,4-dihydroxybenzoic acid (3,4-DHB),3,5-dihydroxybenzoic acid (3,5-DHB), 2,3,4-trihydroxybenzoic acid(2,3,4-THB), 2,4,6-trihydroxybenzoic acid (2,4,6-THB),3,4,5-trihydroxybenzoic acid (3,4,5-THB), 4-hydroxyphenylacetic acid,2-hydroxyisocaproic acid, 3-hydroxycinnamic acid, 3-aminobenzoic acid,4-aminobenzoic acid and combinations thereof.

The naturally occurring sweeteners above can also be in the form ofextracts or concentrated fractions of these extracts, in particularThaumatococcus extracts (Katemfe bush), extracts of Stevia ssp. (inparticular Stevia rebaudiana), Swingle extract (Momordica or Siratiagrosvenorii, Lo han guo), extracts of licorice root, also Glycerrhyziassp. (in particular Glycerrhyzia glabra), Rubus ssp. (in particularRubus suavissimus), citrus extracts, extracts of Lippia dulcis, vanillaextract, sugar beet extract, sugarcane leaf essence, correspondinglyconcentrated fractions of these extracts. U.S. Pat. No. 7,851,005. U.S.Patent Publication No. 20110076239. Kant, Sweet proteins—Potentialreplacement for artificial low calorie sweeteners, Nutrition Journal2005, 4:5. I. Faus, Recent developments in the characterization andbiotechnological production of sweet-tasting proteins, Appl. Microbiol.Biotechnol. 2000, 53: 145-151.

The taste-modifying substance may be water-soluble (i.e., capable ofbeing substantially or completely dissolvable in water) orwater-insoluble (i.e., exhibiting poor or no solubility in water). Insome embodiments, it may be desirable to control the release rate of thetaste-modifying substance. Different release rates may be desireddepending on the type of the gastrointestinal tract preparationcomposition and the consumption time thereof. In some embodiments, therelease rate may be based on the solubility of the taste-modifyingsubstance in water, or based on the formulation of the compositioncontaining the taste-modifying substance.

The taste-modifying substance may be used alone or as part of acomposition, and in any suitable forms well-known in the art, including,but not limited to, free forms, spray-dried forms, powders, beads,liquids, solids, solutions, emulsions, dispersions, encapsulated forms,capsules, tablets, pills, granules, pellets, solids mixtures, gums,lozenges, dispersions in liquid phases, pastes, extracts, fractions orisolates obtained from natural sources and mixtures thereof.

The composition containing the taste-modifying substance may have atleast one pharmaceutical carrier according to conventionalpharmaceutical techniques. The carrier may take a wide variety of formsdepending on the form of the composition. For example, for liquid oralformulations, such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, coloring agents and the like. For solid oralformulations, such as powders, capsules and tablets, suitable carriersand additives include starches, sugars, diluents, granulating agents,lubricants, binders, disintegrating agents and the like.

The taste-modifying substance may be present in amounts ranging fromabout 0.01% to about 100%, from about 0.1% to about 90%, from about 1%to about 80%, from about 5% to about 70%, from about 5% to about 60%,from about 5% to about 50%, from about 5% to about 40%, or from about 5%to about 30% by weight of the composition containing the taste-modifyingsubstance.

The taste-modifying substance may be kept in the subject's (e.g.,patient's) mouth for about 5 seconds to about 30 minutes, about 10seconds to about 20 minutes, about 15 seconds to about 10 minutes, about30 seconds to about 5 minutes, about 1 minute to about 5 minutes, about2 minutes to about 10 minutes, about 1 minutes to about 3 minutes. Thecomposition containing the taste-modifying substance may disintegrate ordissolve in the subject's mouth. The taste-modifying substance may beapplied to the subject's tongue. The taste-modifying substance (or thecomposition containing the taste-modifying substance) may also bechewed.

Miraculin can be considered both a sweet taste-modifying agent and asour taste-modifying agent. In the present invention, miraculin may befrom the miracle fruit, flesh of miracle fruit, miracle fruit granules,miracle berry, miracle berry extracts, frozen miracle berry, frozenmiracle berry extract, dehydrated miracle berry, miracle fruit in powderform, miracle fruit tablets, miracle fruit gum, and miracle berrylollypop. Miraculin may also be produced from any suitable geneticallymodified cells or organism, including, but not limited to, Escherichiacoli, yeast, plants (such as tobacco, lettuce, tomato, etc.), insectcells, and mammalian cells.

Miraculin can also be prepared using the methods described in U.S.Patent Publication No. 20090205068; U.S. Pat. No. 5,886,155; Theerasilet al., Complete Purification and Characterization of theTaste-modifying Protein, Miraculin, from Miracle Fruit, J. Biol. Chem.1988, Vol. 263, No. 23: 11536-11539; Chen et al., The SourTaste-Modifying Protein (Miraculin), Tyrosinase Inhibitors andAntioxidants from Synsepalum dulcificum, Current Nutrition & FoodScience, 2009, 5, 172-179; Matsuyama et al., 2009, Functional expressionof miraculin, a taste-modifying protein in Escherichia coli, J. Biochem.145 (4): 445-50; Sun et al., Functional expression of thetaste-modifying protein, miraculin, in transgenic lettuce, FEBS Lett.2006, 580 (2): 620-6; Kato et al., Molecular Breeding of Tomato Linesfor Mass Production of Miraculin in a Plant Factory. J. Agric. FoodChem. 2010, 58 (17): 9505-10.

The gastrointestinal tract preparation composition of the presentinvention is administered orally, and may be used to prepare any part(s)of the gastrointestinal tract, including, but not limited to, theesophagus, stomach, intestine (or bowel) such as the small intestine andthe large intestine including cecum, colon and rectum.

Bowel preparation compositions, also called bowel cleansers, bowelcleansing compositions purgatives, cathartics, and lavages, areformulated for rapid emptying of the bowel and are intended forshort-term use. Bowel preparation compositions include, for example,colon evacuants and colon cleansing compositions.

The gastrointestinal tract preparation composition of the presentinvention may be isosmotic or hyperosmotic. The gastrointestinal tractpreparation composition may contain one or more electrolytes. Thegastrointestinal tract preparation composition may contain at least onesalt, including, but not limited to, a sodium salt, a potassium salt, acalcium salt, an ammonium salt or mixtures thereof. For example, thesalts may be sodium chloride, potassium chloride, sodium bicarbonate(sodium hydrogen carbonate), sodium sulfate, sodium phosphate ormixtures thereof. The preparation composition may comprise at least onealkali metal salt, and/or at least one alkaline earth metal salt. Thealkali metal may be sodium, potassium, etc. The alkaline earth metal maybe magnesium, calcium, etc.

The gastrointestinal tract preparation composition may contain at leastone sodium phosphate. The composition may have sodium phosphate invarying proportions of monobasic and dibasic species.

The concentration of the salt in the gastrointestinal tract preparationcomposition of the invention may vary depending on the type of the saltand other factors. For example, a liter of the preparation compositionmay contain greater than about 0.2 g, greater than about 0.5 g, greaterthan about 1 g, greater than about 2 g, greater than about 3 g, greaterthan about 5 g, less than about 10 g, less than about 9 g, less thanabout 7.5 g, less than about 7 g, less than about 5 g, less than about 4g, less than about 2 g, less than about 1.5 g of a salt.

The gastrointestinal tract preparation composition may comprisepolyethylene glycol (PEG). The PEG may comprise any food-grade orpharmaceutical-grade PEG. The average molecular weight of PEG may begreater than about 900, greater than about 2000, greater than about2500, less than about 4500, or between about 3000 and about 8000. Forexample, it may be PEG 4000 or PEG 3350. PEG may also be lower molecularweight PEG polymers (such as PEG 400). The PEG used in a composition ofthe invention may comprise one PEG species, or two or more different PEGspecies.

The concentration of PEG in the gastrointestinal tract preparationcomposition of the invention may vary. A liter of the gastrointestinaltract preparation composition of the invention may contain greater thanabout 90 g, greater than about 100 g, less than about 250 g, less thanabout 150 g, less than about 140 g, or less than about 125 g of PEG. Forexample, a composition of the invention may comprise 100 g or 125 g perliter of PEG.

The gastrointestinal tract preparation composition may be administeredover a time period ranging from about 30 minutes to about 3 days, fromabout 1 hour to about 24 hours, from about 2 hours to about 12 hours, orfrom about 1 hour to about 4 hours. The administration time period maybe in a continuous period or a discontinuous period. In discontinuousadministrations, a portion of the composition, for example,approximately half, may be administered the evening before thediagnostic, therapeutic or surgical procedure is to be carried out, withthe remainder of the composition being administered on the day of theprocedure. The preparation composition may be taken once or severaltimes per day on the day of the diagnostic, surgical or therapeuticprocedure, and/or on the day(s) preceding the procedure, depending uponvarious factors, such as the procedure, the degree of cleansingrequired, the patient's condition (e.g., the presence of complicatingbowel conditions such as constipation).

A patient may take the taste-modifying substance every time beforetaking the gastrointestinal tract preparation composition, or may onlytake the taste-modifying substance before taking certain portions of thepreparation composition.

The gastrointestinal tract preparation composition may be a liquid or asolid.

When it is a liquid (e.g., a solution), the dose or volume of thegastrointestinal tract preparation composition to be administered willdepend on the patient being treated. For example, a smaller dose orvolume of preparation solution is appropriate in the treatment of smallchildren and a higher volume of preparation solution is appropriate inadult patients. When the gastrointestinal tract preparation compositionis a liquid, the volume of the preparation composition administered mayrange from about 0.1 liters to about 5 liters, from about 0.2 liters toabout 4.5 liters, from about 0.5 liters to about 4 liters, from about 1liter to about 4 liters, from about 1 liter to about 3 liters, or fromabout 1.5 liters to about 2 liters. A patient may be required to finishall the gastrointestinal tract preparation composition, or may be askedto take the preparation composition until, for example, the rectaleffluent is clear.

When the gastrointestinal tract preparation composition is a solution,it may have any suitable osmolarity, for example, greater than about 330mOsmol/kg, greater than about 350 mOsmol/kg, greater than about 400mOsmol/kg, greater than about 460 mOsmoL/kg, less than about 600mOsmol/kg, less than about 550 mOsmol/kg, less than about 500 mOsmol/kg,less than about 470 mOsmol/kg.

The gastrointestinal tract preparation composition may also beconcentrate compositions, such as, in dry form (e.g., powder, tablet,granular or any other suitable physical form) or in liquid form (e.g.,syrup, suspension or emulsion). The bulk of the liquid component of afinished composition is not present in the concentrate to allow forreduced weight, volume, storage and shipping costs while at the sametime allowing for increased shelf life of the concentrate versus final,diluted composition. When preparing the final, ready-to-administercomposition, the concentrate composition may be diluted by any suitableliquid, such as water, tea, etc.

Non-limiting examples of the commercially available gastrointestinaltract preparation compositions include, but are not limited to, Colyte,GoLYTELY, NuLytely, TriLYTE, HalfLytely, MoviPrep, and MiraLax,GlycoLax, Fleet Phospho-soda, Visicol, OsmoPrep, Fleet, Fleet Enema,Lo-So Prep, GlycoPrep C and Magnesium Citrate. U.S. Patent PublicationNos. 20100196513 and 20040170698. Technology Status Evaluation Report:Colonoscopy Preparation, GASTROINTESTINAL ENDOSCOPY 200969(7):1201-1209.

The present methods may also include administering additional agents tothe patient. For example, for added potency in certain clinicalapplications, a bowel stimulant such as biscodyl or ascorbic acid, orother agent known for its laxative properties may be taken inconjunction with the administration of these compositions asappropriate.

The gastrointestinal tract preparation composition may contain at leastone pharmaceutical carrier according to conventional pharmaceuticaltechniques. The carrier may take a wide variety of forms depending onthe form of preparation desired for administration. For example, forliquid oral preparations such as, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like. For solidoral preparations such as, powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. In someembodiments, the composition may include optional additives such asantioxidants, amino acids, caffeine, emulsifiers, minerals,micronutrients, phytochemicals (“phytonutrients”), stabilizers,thickening agents, medicaments, vitamins, or mixtures thereof.

The pH of a gastrointestinal tract preparation solution (or a liquidcomposition) may be measured using conventional laboratory techniques,such as using a pH meter, pH sensor, pH indicator, pH test paper etc. Incertain embodiments, it is also possible to calculate pH from knowledgeof the components of a solution.

The gastrointestinal tract preparation solution may be acidified by atleast an inorganic acid or an organic acid including, but not limitedto, citric acid, acetic acid and ascorbic acid, phosphoric acid, malicacid, succinic acid, formic acid, fumaric acid, maleic acid, adipicacid, butyric acid, glyconic acid, lactic acid, oxalic acid, tartaricacid and mixtures thereof, or other permitted food acids.

The pH of the gastrointestinal tract preparation solution may also beadjusted by compounds including, but not limited to, ammonium hydroxide,sodium carbonate, potassium carbonate, sodium bicarbonate, carbondioxide, and mixtures thereof.

When adjusting the pH of the composition, the pH may be increased ordecreased by at least about 0.05 pH units, at least about 0.1 pH units,at least about 0.15 pH units, at least about 0.2 pH units, at leastabout 0.3 pH units, at least about 0.4 pH units, or at least about 0.5pH units.

The present methods can be used with a mammal, preferably a human.Mammals include, but are not limited to, primates, simians, domesticanimals, such as feline or canine subjects, farm animals, such as butnot limited to bovine, equine, caprine, ovine, and porcine subjects,research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs,cats, etc.

The following examples of specific aspects for carrying out the presentinvention are offered for illustrative purposes only, and are notintended to limit the scope of the present invention in any way.

Example 1

Eleven subjects participated in the tasting experiment. All subjectswere non-smokers with no known abnormalities in taste perception. Nosubject was on any medication which would alter taste perception.

The various tasting solutions (Nos. 1-3 as listed below) were preparedusing commercially available colon prep, NuLytely (BraintreeLaboratories Inc.). The NuLytely preparation was mixed according to thepackage insert using drinking water. According to the manufacturer'sprescribing information, NuLytely powder contains 420 g polyethyleneglycol 3350 (PEG-3350), 5.72 g sodium bicarbonate, 11.2 g sodiumchloride, and 1.48 g potassium chloride. When made up to 4 liters volumewith water, the solution contains 31.3 mmol/L PEG-3350, 65 mmol/Lsodium, 53 mmol/L chloride, 17 mmol/L bicarbonate and 5 mmol/Lpotassium. Sample No. 1 contained only the NuLytely preparation; sampleNo. 2 contained the NuLytely preparation and the ingredients in theflavor pack that accompanied the NuLytely powder (provided by themanufacturer).

32 ounces of each sample were prepared on the day of the tastingexperiment and the pH of each sample measured. The samples were keptrefrigerated until the start of the tasting experiment.

The pH of the samples was measured using a digital waterproof pH meter,HM Digital pH meter PH-200. The pH meter was calibrated with a standardpH 7.0 reference solution made by General Hydroponics. The device wascalibrated prior to measurements.

The pH of each sample was again measured 5 minutes prior to the start ofthe experiment. There was no change in the pH from the time of samplepreparation. The solutions contained no precipitate.

The pH of tasting sample No. 3 was adjusted to 4.8 using a commerciallyavailable flavor pack. This flavor pack was a sugar-free, lemonadeflavor packet, Kool-Aid unsweetened soft drink mix (Kraft). According tothe manufacturer's packet insert, the powder in the flavor packetcontained citric acid, calcium phosphate, maltodetrin, salt and lessthan 2% of natural flavor and preservatives. In addition to the lemonadeflavor pack, 1.8 ml of commercially available lemon extract (McCormick &Co.) was added to the 4-liter NuLytely preparation mixture. The lemonextract contained alcohol, water and oil of Lemon. The pH was againchecked after all the components were added and was confirmed to remainpH 4.8.

No. 1: Original Nulytely prep with no flavor pack pH 8.0 No. 2: Nulytelyprep with flavor pack pH 8.0 No. 3: Nulytely prep with lemonade powderand pH 4.8 lemon extract

Tasting Experiment

The eleven subjects each received 2 ounces of the sample and tasted it.They started with sample No. 1, followed by the remaining sample Nos. 2through 3.

Tasting sample No. 3 was tasted with miracle berry tablets. The subjectswere given one Mberry Miracle Fruit Tablet (400 mg per serving,distributed by My M Fruit LLC). An Mberry tablet contained miracle fruitpowder and corn starch. The package instructions were followed and thetablet was placed on the subject's tongue and was allowed to dissolve inthe mouth over a period of 5 minutes. After each tablet had completelydissolved, the subjects were given 2 ounces of the tasting sample.

For each of tasting sample Nos. 1-3, the sample was rated by thesubjects in terms of saltiness. Each subject acted as their own control.The scale used to rate each sample was from 0 to 10. For saltiness, zerois the least salty and 10 very salty.

The subjects tasted every sample twice and rated saltiness each time.All of the ratings were recorded on a data collection sheet and keptblind to the other subjects.

The data sheets were collected from all eleven subjects. The averagerating for saltiness for was calculated. See Table 2 and FIG. 1.

TABLE 2 No. 3 M Berry/ No. 1 No. 2 Nulytely/ Lemonnade powder NulytelyProvided Flavor Pack and lemon extract Saltiness 5.4 4.2 1.9

Results

The saltiness of the preparation solution was significantly diminishedafter the use of miracle berry.

Example 2

This study will involve the standard PEG colonoscopy preparationcurrently on the market with the addition of an unsweetened lemonadeflavor pack which contains citric acid.

The patient will be dissolving a freeze-dried Miracle fruit tablet ontheir tongue prior to consumption of the preparation, which will affectthe patient's perception of taste.

Patient Selection

Patients scheduled for screening colonoscopies will be considered forthe study. Patients may or may not have had previous colonoscopy.Patients with any abnormality or dysfunction in taste will be excludedfrom the study. Likewise exclusion criteria will also include patientswho have had colonic, small bowel or gastric surgery as this may alter apatient's ability to tolerate the preparation. Patients with diagnosisof dry mouth, xerostomia, etc. will be excluded from the study. Theindication for performing the colonoscopy should not be directed atspecific diagnostic complaint but rather be indicated for the purpose ofscreening or surveillance. Patients with specific gastrointestinalcomplaints will be excluded from the study.

Study Design

At least one week prior to colonoscopy, patients taking a blood thinner,e.g., Coumadin, Plavix, must contact the ordering provider (e.g., aphysician) for approval to stop the medication.

3 days prior to colonoscopy procedure, patients will be instructed tostop taking all herbal supplements, vitamins and iron; continue to taketheir daily prescribed medications, except for blood thinners as notedabove; do not eat raw fruits or raw vegetables (cooked or cannedfruit/vegetables are allowed); do not consume corn, peas, seeds, popcornor nuts.

1 day prior to the procedure, 4-liter Colyte will be mixed andrefrigerated if desired. Note Colyte must be ingested within 24 hoursonce mixed. Patients will not be allowed to begin to drink Colyte until6 pm. The patients are instructed to drink clear liquids only all day,including breakfast, lunch and dinner. No solid food, dairy or alcoholwill be allowed. Nothing red or purple will be allowed. The patients mayhave apple juice, white cranberry or grape juice, popsicles, jello,Italian ice, ginger ale, sprite, black coffee or tea, Gatorade. Thepatients need to drink 8 oz of clear liquid every hour between 11 am and5 pm.

At 6 pm, the patients will drink one 8-oz glass of Colyte. The patientswill be asked to complete a questionnaire rating the sweetness,saltiness and palatability of the Colyte preparation (FIG. 2), prior toadding a flavor packet or dissolving the miracle fruit tablet on thetongue.

After completion of the questionnaire in FIG. 2, the patients will addthe flavor packet to the remaining Colyte preparation and mix well. Thepatients will then place one Miracle Berry tablet in the mouth and letit dissolve on the tongue over 3-5 minutes. The tablet cannot be chewed.This process of dissolving a tablet on the tongue will be repeated every30 minutes during the time the patient is required to drink thepreparation.

The patients will drink the first 8 oz of the newly mixed preparation,and then complete the second patient questionnaire, rating thesweetness, saltiness and palatability of the preparation (FIG. 3).

The patients will continue to drink one 8-oz preparation every 10minutes until half of the 4-liter Colyte preparation solution isconsumed. The remaining half of the preparation will be saved fordrinking 5 hours prior to the procedure the next day. The consumption ofhalf of the preparation likely will require between 1-4 miracle fruittablets to be used every 30 minutes.

On the day of the procedure, 5 hours prior to the procedure, thepatients will dissolve a miracle fruit tablet on the tongue over 3-5minutes, and then drink 8 oz of Colyte. This will be repeated every 10minutes until all the Colyte is consumed.

The patients will complete the post-preparation questionnaire (FIG. 4).Nothing is allowed in patients' mouth 2 hours prior to colonoscopy, noteven clear liquid.

The patients will be instructed to take no diuretics or diabetic pillsthe morning of the colonoscopy procedure. Other prescribed medicallynecessary prescription can be taken with a sip of water at least 2 hoursprior to colonoscopy. The patients need to have an adult 18 years orolder to drive and accompany home.

Endoscopic Evaluation

Quality of colonic cleansing will be assessed by asking attendinggastroenterologists in the outpatient endoscopy unit to complete aquestionnaire immediately after the procedure designed to assess thequality of colonic mucosa visualization. Endoscopic visibility will beassessed for the amount of air bubbles in the colon and the adequacy ofthe colon preparation. The endoscopists will be instructed not to askthe patients about the details of their bowel preparations.

The questionnaire will ask the endoscopists to evaluate the quality ofvisualization as previously shown in S. Tongprasert et al., ImprovingQuality of Colonoscopy by Adding Simethicone to Sodium Phosphate BowelPreparation, World Journal of Gastroenterology, 2009, 15(24): 3032-3037and J. Johanson et al., A Randomized, Multicenter Study Comparing theSafety and Efficacy of Sodium Phosphate Tablets with 2 L PolyethyleneGlycol Solution Plus Bisacodyl Tablets for Colon Cleansing, AmericanJournal of Gastroenterology, 2007; 102: 2238-2246. The overall qualityof visualization and the colonic cleansing will be based on (1) theamount of stool (liquid, semisolid, or solid) observed during theprocedure and (2) the amount of “colonic contents” (including allliquid, semisolid, and solid material in the lumen of the colon)observed during the procedure rather than only “stool.” Endoscopistswill evaluate the visualization as follows: “excellent” means “smallamounts of clear liquid, >90% mucosa seen, minimal suctioning needed foradequate visualization”; “good” means “residual liquid stool, >90%mucosa seen, significant suctioning needed for adequate visualization”;“adequate” means “some particulate matter, >90% of mucosa seen, mixtureof liquid and semisolid stool which could be suctioned and/or washed”;“poor” means “substantial particulate matter or solid stool, <90% ofmucosa seen, mixture of semisolid and solid stool, which could not besuctioned or washed”; and “unacceptable” means “solid stool through thecolon.”

Endoscopists will also be asked to estimate the amount of time theyspent suctioning fluid and feces from the colon and time spent washingthe colon to clean the mucosa relative to the total examination time.Endoscopists will be estimating the time spent suctioning and cleaningrelative to the total examination time on a 4-degree scale: “0” means“almost no time spent, <2% of total examination time”; “1” means“minimal time spent, between 2%-8% of total examination time”; “2” means“some time spent, between 8%-15% of total examination time”; and “3”means “large amount of time spent, >15% of total examination time.”

Five areas of the colon (rectosigmoid, descending, transverse,ascending, and cecum) will also be evaluated for the amount of airbubbles. As previously shown in S. Tongprasert et al., Improving Qualityof Colonoscopy by Adding Simethicone to Sodium Phosphate BowelPreparation, World Journal of Gastroenterology, 2009, 15(24): 3032-3037,the amount of intraluminal air bubbles will be classified into fourgrades: “0” means “no or minimal scattered bubbles”; “1” means “bubblescovering at least half the luminal diameter”; “2” means “bubblescovering the circumference of the lumen”; and “3” means “bubbles fillingthe entire lumen.”

The success rate of the colonoscopies, total duration of colonoscopiesand endoscopist satisfaction will be evaluated and compared between thetwo groups. Endoscopist satisfaction will be evaluated for air bubblesand adequacy of colon preparation by a self-rated questionnaire with a4-degree scale: “0” means “very poor”; “1” means “poor”; “2” means“good”; and “3” means “very good.”

Results

The results of this study will show that patients who took thegastrointestinal tract preparation with the miracle berry tabletcomplied with the requirements of the bowel preparation better thanpatients who took the preparation alone. These results will also showthat the patients who took the gastrointestinal tract preparationsolution with the miracle berry tablet had a more successful colonoscopycompared to those patients who took the preparation alone.

Tolerability and Satisfaction

The patients who have taken the gastrointestinal tract preparationsolution with the miracle berry tablet will report that they ingested asignificantly higher volume (e.g., 3.9 to 4 liters on average) of thefluid during the preparation period as compared to the patients who tookthe gastrointestinal tract preparation solution alone (e.g., 3 liters onaverage). The overall tolerability of the two preparation methods willalso differ.

Not only will patients who have consumed the gastrointestinal tractpreparation solution with the miracle berry tablet be more satisfiedthan patients who take the preparation alone, but also, patients whohave consumed the gastrointestinal tract preparation solution with themiracle berry tablet will evaluate the preparation to be sweet andpalatable and those who have consumed the preparation alone willevaluate the preparation to be foul-tasting and salty. In addition,endoscopists will also evaluate the colonoscopic examinations ofpatients who have consumed the gastrointestinal tract preparationsolution with the miracle berry tablet to be more satisfactory comparedto patients who have consumed the preparation without the miracle berrytablet. The data will be analyzed using standard statistical criteria.

Endoscopic Evaluation of Colonic Mucosa

Endoscopists who performed the colonoscopies will report that there is adifference in quality of visualization of the colonic mucosa betweenpatients who took the gastrointestinal tract preparation solution withthe miracle berry tablet(s) and those who took the preparation alone.The quality of colonic mucosa will be significantly better in the groupof patients who took the gastrointestinal tract preparation solutionwith the miracle berry tablet(s) than in the group of patients who tookthe preparation alone. These endoscopists will report that there wasclearer visualization of the colonic mucosa in patients who took thegastrointestinal tract preparation solution with the miracle berrytablet(s) compared to patients who took the preparation alone. They willalso report that there were less intraluminal bubbles in areas of thecolon in patients from the former group than the latter group and lesstime was spent suctioning fluid and feces from the colon and washing thecolon to clean the mucosa. There will also be a higher success rate ofcompleted colonoscopies and a shorter amount of time needed to completethe colonoscopy for patients who took the gastrointestinal tractpreparation solution with the miracle berry tablet(s) than those whotook the preparation alone.

Example 3

Four subjects, 30 to 55 years old, participated in the tastingexperiment. They were three males and one female with no knownabnormalities in taste perception. All subjects were non-smokers. Nosubject was on any medication which would alter taste perception.

The various tasting solutions (Nos. 1-6 as listed below) were preparedusing a commercially available colon prep, HalfLytely (BraintreeLaboratories Inc.). The HalfLytely preparation was mixed according tothe package insert using drinking water. The flavor packet provided bythe manufacturer was not used in the tasting experiment.

16 ounces of each sample were prepared the evening prior to the tastingexperiment and the pH of each sample measured. The samples were keptrefrigerated overnight until the start of the tasting experiment.

The pH of the samples was measured using a digital waterproof pH meter,HM Digital pH meter PH-200, with the below settings:

pH Range: 0-14

Temperature Range: 0-80° C.; 32-176° F.

Resolution: 0.01 pH; Temperature resolution is 0.1° C./F.

Accuracy: +/−0.02 pH; Temperature accuracy is +/−2%

Calibration: Digital automatic calibration (one point) with digital finetuning

Electrode: Replaceable glass sensor and reference tube electrodes

Housing: IP-67 Waterproof (submersible; floats)

Power source: 3×1.5V button cell batteries

Dimensions: 18.5×3.4×3.4 cm

Weight: 96.4 g (3.4 oz)

The pH meter was calibrated with a standard pH 7.0 reference solutionmade by General Hydroponics. The device was calibrated prior tomeasurements.

On the day of the tasting experiment, the pH of each sample was againmeasured 5 minutes prior to the start of the experiment. There was nochange in the pH from the time of sample preparation the night prior.The solutions contained no precipitate after overnight storage.

The pH of the tasting samples was adjusted by using a commercialsugar-free, lemonade flavor packet, Kool-Aid unsweetened soft drink mix(Kraft). According to the manufacturer's packet insert, the powder inthe flavor packet contained citric acid, calcium phosphate, maltodetrin,salt and less than 2% of natural flavor and preservatives. Whennecessary, the Kool-Aid powder was added to the tasting samples untilthe desired pH was reached. The pH in each of the six tasting sampleswas as follows:

No. 1 Original prep with no Kool-Aid powder added pH 8.0 No. 2 Tastingsample pH 7.0 No. 3 Tasting sample pH 6.0 No. 4 Tasting sample pH 5.0No. 5 Tasting sample pH 4.0 No. 6 Tasting sample pH 3.0

Tasting Experiment: Without Miracle Berry

The four subjects each received 2 ounces of the sample and tasted it.They started with the most basic solution above (sample No. 1, pH 8),followed by the remaining solutions 2 through 6. The sample was thenrated by the subjects in terms of sweetness, saltiness and overallpalatability. Each subject acted as their own control.

The scale used to rate each sample was from 0 to 10. For sweetness, zerois the least sweet and 10 very sweet; for saltiness, zero is the leastsalty and 10 very salty; for overall palatability, zero is the leastpalatable and 10 most palatable.

The subjects tasted every sample twice and rated sweetness, saltinessand overall palatability each time. All of the ratings were recorded ona data collection sheet and kept blind to the other subjects.

This arm of the experiment was conducted over a 20-minute time period.

The data sheets were collected from all four subjects. The averagerating in each of the three categories (sweetness, saltiness and overallpalatability) for each of the tasting samples from the four subjects wascalculated (Table 3 and FIG. 5)

TABLE 3 pH 8 pH 7 pH 6 pH 5 pH 4 pH 3 Sweetness 0 0 0 0.5 0.75 1Saltiness 6.75 7.75 7 6.25 5.5 4.6 Palatability 1.5 1.25 2.25 2.75 3 3

With Miracle Berry

The four subjects were then given one Miracle Frooties tablet (600 mgper serving) produced by The Great Green Miracle Fruit Farm Ltd. AMiracle Frooties tablet contained the following: dried miracle fruitpulp, potato starch, microcrystalline cellulose, dibasic calciumphosphate and magnesium stearate.

The package instructions were followed and the miracle fruit tablet wasplaced on the subject's tongue and was allowed to dissolve in the mouthover a period of 5 minutes.

After each tablet had completely dissolved, tasting of the six tastingsamples was again conducted as described above. The subjects were given2 ounces of tasting samples and rated the samples according tosweetness, saltiness or overall palatability. The same 0-10 scale wasused in this arm of the experiment. The ratings were recorded and keptblind to the other subjects.

This arm of the experiment was conducted over a 20-minute time period.

The data sheets were collected from all four subjects. The averagerating in each of the three categories (sweetness, saltiness and overallpalatability) for each of the tasting samples from the four subjects wasagain calculated (Table 4 and FIG. 6).

TABLE 4 pH 8 pH 7 pH 6 pH 5 pH 4 pH 3 Sweetness 0 0 1 5.5 7.75 9.5Saltiness 6.25 7 6 2.5 2.5 2 Palatability 1.5 1.5 2 7 5.75 3

Results

The overall palatability of the preparation solution was greatlyimproved after the use of miracle berry tablet in an acidic environment.With miracle berry, the pH 5 solution was considered to be the mostpalatable prep solution.

The saltiness of the preparation solution was significantly diminishedafter the use of miracle berry with the pH solutions between 3-5 beingconsidered the least salty.

The sweetness of the preparation solution was greatly improved after theuse of miracle berry tablet in an acidic environment. With miracleberry, the pH 3 solution was considered to be the sweetest.

Example 4

Eleven subjects participated in the tasting experiment. All subjectswere non-smokers, with no known abnormalities in taste perception. Nosubject was on any medication which would alter taste perception.

The various tasting solutions (Nos. 1-4 as listed below) were preparedusing a commercially available colon prep, NuLytely (BraintreeLaboratories Inc.). The NuLytely preparation was mixed according to thepackage insert using drinking water. According to the manufacturer'sprescribing information, NuLytely powder contains 420 g polyethyleneglycol 3350 (PEG-3350), 5.72 g sodium bicarbonate, 11.2 g sodiumchloride, and 1.48 g potassium chloride. When made up to 4 liters volumewith water, the solution contains 31.3 mmol/L PEG-3350, 65 mmoL/Lsodium, 53 mmoL/L chloride, 17 mmol/L bicarbonate and 5 mmol/Lpotassium.

Sample No. 1 contained only the NuLytely preparation; sample No. 2contained the NuLytely preparation and the ingredients in the flavorpack that accompanied the NuLytely powder (provided by themanufacturer).

32 ounces of each sample were prepared on the day of the tastingexperiment and the pH of each sample measured. The samples were keptrefrigerated until the start of the tasting experiment.

The pH of the samples was measured using a digital waterproof pH meter,HM Digital pH meter PH-200. The pH meter was calibrated with a standardpH 7.0 reference solution made by General Hydroponics. The device wascalibrated prior to measurements.

The pH of each sample was again measured 5 minutes prior to the start ofthe experiment. There was no change in the pH from the time of samplepreparation. The solutions contained no precipitate.

The pH of tasting sample Nos. 3 and 4 was adjusted to 4.8 by using acommercially available flavor pack. This flavor pack was a sugar-free,lemonade flavor packet, Kool-Aid unsweetened soft drink mix (Kraft).According to the manufacturer's packet insert, the powder in the flavorpacket contained citric acid, calcium phosphate, maltodetrin, salt andless than 2% of natural flavor and preservatives. For sample No. 3, inaddition to the lemonade flavor pack, 1.8 ml of commercially availablelemon extract (McCormick & Co.) was added to the NuLytely 4-literpreparation mixture. For sample No. 4, in addition to the lemonadeflavor pack, 1.8 ml of lemon extract (McCormick & Co.) and 1.8 ml ofcommercially available orange extract (McCormick & Co.) were added tothe NuLytely 4-liter preparation mixture. The lemon extract (McCormick &Co.) contained alcohol, water and oil of lemon; the orange extract(McCormick & Co.) contained alcohol, water and oil of orange. The pH oftasting sample Nos. 3 and 4 was checked again after all the componentswere added and was confirmed to remain pH 4.8.

No. 1: Original Nulytely prep with no flavor pack pH 8.0 No. 2: Nulytelyprep with flavor pack pH 8.0 No. 3: Nulytely prep with lemonade powderand pH 4.8 lemon extract No. 4: Nulytely prep with lemonade powder andpH 4.8 lemon/orange extracts

Tasting Experiment

The eleven subjects each received 2 ounces of the sample and tasted it.They started with sample No. 1, followed by the remaining solutions 2through 4.

Tasting sample Nos. 3 and 4 were tasted with miracle berry tablets. Thesubjects were given one Mberry, Miracle Fruit Tablet (400 mg perserving) distributed by My M Fruit LLC. An Mberry tablet containedmiracle fruit powder and corn starch. The package instructions werefollowed and the miracle fruit tablet was placed on the subject's tongueand was allowed to dissolve in the mouth over a period of 5 minutes.After each tablet had completely dissolved, the subjects were given 2ounces of the tasting samples.

For each sample tasting, the sample was rated by the subjects in termsof sweetness and overall palatability. Each subject acted as their owncontrol. The scale used to rate each sample was from 0 to 10. Forsweetness, zero is the least sweet and 10 very sweet; for overallpalatability, zero is the least palatable and 10 most palatable.

The subjects tasted every sample twice and rated sweetness and overallpalatability each time. All of the ratings were recorded on a datacollection sheet and kept blind to the other subjects.

The data sheets were collected from all eleven subjects. The averagerating in each of the two categories (sweetness and overallpalatability) for each of the tasting samples from the eleven subjectswas calculated. See Table 5 and FIG. 7.

TABLE 5 No. 2 No. 3 No. 4 No. 1 Nulytely/ M Berry M Berry NulytelyProvided Mix Lemon Lemon/Orange Sweetness 0.8 2.5 6.7 6.6 Palatability2.9 3.3 7.1 7.5

Results

The overall palatability and sweetness of the preparation solution weregreatly improved after the use of miracle berry tablet in an acidicenvironment (e.g., pH 4.8 in this experiment).

The scope of the present invention is not limited by what has beenspecifically shown and described hereinabove. Those skilled in the artwill recognize that there are suitable alternatives to the depictedexamples of materials, configurations, constructions and dimensions.Numerous references, including patents and various publications, arecited and discussed in the description of this invention. The citationand discussion of such references is provided merely to clarify thedescription of the present invention and is not an admission that anyreference is prior art to the invention described herein. All referencescited and discussed in this specification are incorporated herein byreference in their entirety. Variations, modifications and otherimplementations of what is described herein will occur to those ofordinary skill in the art without departing from the spirit and scope ofthe invention. While certain embodiments of the present invention havebeen shown and described, it will be obvious to those skilled in the artthat changes and modifications may be made without departing from thespirit and scope of the invention. The matter set forth in the foregoingdescription and accompanying drawings is offered by way of illustrationonly and not as a limitation.

1. A method for reducing a salty taste of a liquid composition for asubject, the method comprising the steps of: (a) determining the pH ofthe liquid composition which has a salty taste, wherein the pH rangesfrom about 1 to about 6.9 or is adjusted to range from about 1 to about6.9; (b) providing miraculin to the subject; and (c) administeringorally the liquid composition to the subject after step (b).
 2. Themethod of claim 1, wherein the liquid composition is a gastrointestinaltract preparation composition to cleanse the gastrointestinal tract ofthe subject.
 3. The method of claim 2, wherein the gastrointestinaltract is the intestine and the gastrointestinal tract preparationcomposition is a bowel preparation solution.
 4. The method of claim 2,wherein the gastrointestinal tract is cleansed prior to carrying out adiagnostic, therapeutic and/or surgical procedure on the patient.
 5. Themethod of claim 2, wherein the gastrointestinal tract is cleansed priorto an endoscopy.
 6. The method of claim 5, wherein the endoscopy is acolonoscopy or sigmoidoscopy.
 7. The method of claim 2, wherein thegastrointestinal tract is cleansed prior to a barium enema examination,capsule endoscopy, virtual colonoscopy, colon surgery orgastrointestinal tract surgery.
 8. The method of claim 1, whereinmiraculin comprises miracle fruit, flesh of miracle fruit, miracle fruitgranules, miracle berry, miracle berry extracts, miracle fruit tablets,miracle berry tablets, or miraculin produced by a genetically modifiedorganism.
 9. The method of claim 1, wherein miraculin is provided to thesubject from about 1 minute to about 1 hour before the liquidcomposition is administered.
 10. The method of claim 9, whereinmiraculin is provided from about 5 minutes to about 30 minutes beforethe liquid composition is administered.
 11. The method of claim 1,wherein the salty taste of the liquid composition is reduced by at leastabout 20% compared to the salty taste of the liquid composition hadmiraculin not been provided.
 12. The method of claim 1, wherein the stepto determine the pH of the liquid composition is carried out prior to orafter the step of providing miraculin to the patient.
 13. The method ofclaim 1, wherein the pH ranges from about 3 to about 6.4.
 14. The methodof claim 1, wherein the pH ranges from about 4 to about 6.4.
 15. Themethod of claim 1, wherein the pH of the liquid composition is adjustedby at least an inorganic acid or an organic acid.
 16. The method ofclaim 15, wherein the acid is selected from the group consisting ofcitric acid, acetic acid, ascorbic acid, phosphoric acid, malic acid,succinic acid, formic acid, fumaric acid, maleic acid, or mixturesthereof.
 17. The method of claim 1, wherein the pH of the liquidcomposition is adjusted by a compound selected from the group ofammonium hydroxide, sodium carbonate, potassium carbonate, sodiumbicarbonate, carbon dioxide, and mixtures thereof.
 18. The method ofclaim 2, wherein the gastrointestinal tract preparation compositioncomprises a potassium salt, a sodium salt, a calcium salt, an ammoniumsalt or mixtures thereof.
 19. The method of claim 2, wherein thegastrointestinal tract preparation composition comprises at least onesodium phosphate.
 20. The method of claim 2, wherein thegastrointestinal tract preparation composition comprises sodiumchloride, potassium chloride, and sodium bicarbonate (sodium hydrogencarbonate), sodium sulfate or mixtures thereof.
 21. The method of claim2, wherein the gastrointestinal tract preparation composition comprisesat least one alkali metal salt, and/or at least one alkaline earth metalsalt.
 22. The method of claim 21, wherein the alkali metal is sodium orpotassium.
 23. The method of claim 21, wherein the alkaline earth metalis magnesium or calcium.
 24. The method of claim 2, wherein thegastrointestinal tract preparation composition is a solution, andwherein the volume of the gastrointestinal tract preparation compositionranges from about 0.1 liters to about 5 liters.
 25. The method of claim2, wherein the gastrointestinal tract preparation composition comprisespolyethylene glycol (PEG).
 26. The method of claim 1, wherein miraculinis provided in the form of a capsule, a tablet, a pill, granules,powders, a pellet, a solids mixture, a solution, a dispersion, anemulsion, a paste, an extract, or an isolate from a natural source.